Mutations in four genes that encode components of mitogenic signaling pathways have been identified in human lung adenocarcinomas,including the EGFR, KRAS, HER2, and BRAF. Genetic models demonstrate that the activating mutations of KRAS, EGFR, and BRAF play a role in the pathogenesis of these tumors. These data suggest that agents that inhibit the function of these oncoprpteins could be important therapeutic agents in this disease. This is borne out by the clinical antitumor activity of EGFR inhibitors in tumors with EGFR mutation. Mutant KRAS is the most common of these lesions (detected in 25% ofadenocarcinomas), but unfortunately there is currently no drug that effectively inhibits this oncoprotein. The goal of this proposal is the development of therapeutic strategies that inhibit KRAS function. We hypothesize that advanced lung adenocarcinomas with mutant KRAS are still dependent on its function and that its effects are mediated by one or more of the KRAS effector proteins. These include RAF, PI3KCA, RAL-GDSand others. Our preliminary data show that a subset of lung adenocarcinomacell lines is sensitive to inhibition of MEK kinase, the downstreamtarget of RAF. Furthermore, tumors in which both KRAS and PI3KCA (encoding the P110alpha catalytic subunit of PI3K) are mutated are resistant to inhibition of either MEK or PI3K but sensitive to combined inhibition of both targets. We hypothesize lung adenocarcinomasthat are KRAS- mutant and PI3KCA wild type will be sensitive to MEK inhibition alone, and that additional tumors will be sensitive to combined inhibition of both the MEK/MAPK and PI3K/AKT pathways. We propose now to determine the dependence of mutant KRAS lung cancer cell lines on expression of KRAS and its effector- molecules, investigate the mechanisms underlying the MEK and PI3K dependence of these tumors, and determine the biologic and potential therapeutic consequences of MEK and PI3K/AKT inhibitors, alone and in combination, in lung adenocarcinomas.The eventual goal is the development of a strategy for the treatment of KRAS-dependent lungadenocarcinoma.